1. Field of the Invention
The invention relates to a process for the preparation of racemic and diastereomeric oxazaphosphorine-2-amines (N-substituted tetrahydro-2H-.sigma..sup.4.lambda..sup.5 -1,3,2-oxazaphosphorine-2-amino-2-oxides [sic]) of the general formula 1 ##STR2##
in which R.sub.1 can be H, 2-bromoethyl, 2-chloroethyl, 2-hydroxyethyl, 2-mesyloxyethyl and 1-phenylethyl, R.sub.2 can be H and 2-chloroethyl and R.sub.3 can be H, 2-bromoethyl, 2-chloroethyl and 1-phenylethyl, or R.sub.1 and R.sub.2, together with the linked N atom, form an aziridine ring. The compounds prepared by the novel process are either cytostatics or immunosuppressants themselves or starting compounds for the preparation of racemic and enantiomerically pure oxazaphosphorine-2-amines having cytostatic or immunosuppressant activity.
2. Background Information
The compounds of the formula 1 include the known medicaments cyclophosphamide (R.sub.1 =R.sub.2 =2-chloroethyl, R.sub.3 =H), ifosfamide (R.sub.1 =R.sub.3 =2-chloroethyl, R.sub.2 =H) and trofosfamide (R.sub.1 =R.sub.2 =R.sub.3 =2-chloroethyl). They have been used in cancer therapy since 1958 or the 1970s (N. Brock, Cancer Res. 49, 1-7 (1989)). Their synthesis is described in the Patent Specifications DE 1 057 119, GB 1 235 022 and DE 1 645 921. The compounds according to formula 1 furthermore include sufosfamide (R.sub.1 =2-mesyloxyethyl, R.sub.2 =H, R.sub.3 =2-chloroethyl), which was developed as an immunosuppressant for autoimmune diseases (DE 2 107 936, DE-A 2 201 675), as well as compounds which are suitable for the preparation of the mentioned oxazaphosphorine-2-amines in their racemic or enantiomeric form (K. Pankiewicz et al., J. Amer. Chem. Soc. 101, 7712-7718 (1979) and K. Misiura et al. J. Med. Chem. 26, 674-679 (1983)).
It is common to the syntheses known from the literature that, as a phosphorus-containing starting compound, 2-chlorotetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide, bis(2-chloroethyl)dichlorophosphoramide or 2-chloro-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-amino-2-o xide [sic] is reacted in one synthesis step to give oxazaphosphorine-2-amine. The three phosphorus-containing starting compounds are prepared, for their part, from phosphoryl chloride (R. H. Iwamato et al. J. Org. Chem. 26, 4743-4745 (1961), O. M. Friedman et al., J. Amer. Chem. Soc. 76, 655-658 (1954) and J. M. S. van Maanen et al., J. Labelled Compd. Radiopharm. 18, 385-390 (1981)).
These syntheses have disadvantages. The total yield of the oxazaphosphorine-2-amines, based on phosphoryl chloride, remains significantly below 50% and is therefore relatively low for a two-stage synthesis. Furthermore, the isolation of the intermediate, i.e. one of the three abovementioned phosphorus-containing starting compounds, is unfavorable, since they are thermally and hydrolytically unstable and can give rise to side reactions during preparation, storage or shortly before use. Additionally, the advantages of a two-stage one-pot reaction are not utilized.